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Reversible Valproate-Induced Subacute Encephalopathy Associated With a MT-ATP8 Variant in the Mitochondrial Genome.

ABSTRACT: Introduction: There are several reported cases of patients developing motor and cognitive neurological impairment under treatment with valproic acid (VPA). We describe a woman who developed a subacute encephalopathy after VPA intake, harboring a mitochondrial DNA variant, previously described as causing VPA sensitivity in one pediatric patient. Material and Methods: A 65-year old woman developed a progressive, severe neurological deterioration after a 3 month treatment with valproate sodium, 800 mg daily. Magnetic resonance spectroscopy (MRS), muscle histochemical analysis and assay of mitochondrial enzymatic activities, and mitochondrial DNA sequencing were performed. Results: Neurological examination showed drowsiness, vertical gaze palsy, inability to either stand or walk, diffuse weakness, increased tendon reflexes. Blood lactate was increased, EEG showed diffuse theta and delta activity, MRI subcortical atrophy and leukoencephalopathy, MRS marked reduction of the NAA spectrum, with a small signal compatible with presence of lactate. Muscle biopsy evidenced presence of ragged red fibers (20%) and reduced COX reactivity. Assay of the muscle enzymatic activities showed multiple deficiencies of the electron transport chain and reduced ATP production. The mt.8393C>T variant in the MT-ATP8 gene was found in homoplasmy. The patient considerably improved after valproate withdrawal. Conclusion: The variant we found has been reported both as a polymorphism and, in a single patient, as related to the valproate-induced encephalopathy. The present case is the first bearing this mutation in homoplasmy. In case of neurological symptoms after starting VPA therapy, once hyperammonemia and liver failure have been ruled out, mtDNA abnormalities should be considered.

SUBMITTER: De Michele G

PROVIDER: S-EPMC6125373 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Reversible Valproate-Induced Subacute Encephalopathy Associated With a MT-ATP8 Variant in the Mitochondrial Genome.

De Michele Giovanna G Sorrentino Pierpaolo P Nesti Claudia C Rubegni Anna A Ruggiero Lucia L Peluso Silvio S Antenora Antonella A Quarantelli Mario M Filla Alessandro A De Michele Giuseppe G Santorelli Filippo M FM

Frontiers in neurology 20180830

Introduction: There are several reported cases of patients developing motor and cognitive neurological impairment under treatment with valproic acid (VPA). We describe a woman who developed a subacute encephalopathy after VPA intake, harboring a mitochondrial DNA variant, previously described as causing VPA sensitivity in one pediatric patient. Material and Methods: A 65-year old woman developed a progressive, severe neurological deterioration after a 3 month treatment with valproa ...[more]

PMID: 30214424

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Project description:BackgroundTo date, mitochondrial genomes of more than one hundred flatworms (Platyhelminthes) have been sequenced. They show a high degree of similarity and a strong taxonomic bias towards parasitic lineages. The mitochondrial gene atp8 has not been confidently annotated in any flatworm sequenced to date. However, sampling of free-living flatworm lineages is incomplete. We addressed this by sequencing the mitochondrial genomes of the two small-bodied (about 1 mm in length) free-living flatworms Stenostomum sthenum and Macrostomum lignano as the first representatives of the earliest branching flatworm taxa Catenulida and Macrostomorpha respectively.ResultsWe have used high-throughput DNA and RNA sequence data and PCR to establish the mitochondrial genome sequences and gene orders of S. sthenum and M. lignano. The mitochondrial genome of S. sthenum is 16,944 bp long and includes a 1,884 bp long inverted repeat region containing the complete sequences of nad3, rrnS, and nine tRNA genes. The model flatworm M. lignano has the smallest known mitochondrial genome among free-living flatworms, with a length of 14,193 bp. The mitochondrial genome of M. lignano lacks duplicated genes, however, tandem repeats were detected in a non-coding region. Mitochondrial gene order is poorly conserved in flatworms, only a single pair of adjacent ribosomal or protein-coding genes - nad4l-nad4 - was found in S. sthenum and M. lignano that also occurs in other published flatworm mitochondrial genomes. Unexpectedly, we unambiguously identified the full metazoan mitochondrial protein-coding gene complement including atp8 in S. sthenum and M. lignano. A subsequent search detected atp8 in all mitochondrial genomes of polyclad flatworms published to date, although the gene wasn't previously annotated in these species.ConclusionsManual, but not automated genome annotation revealed the presence of atp8 in basally branching free-living flatworms, signifying both the importance of manual data curation and of diverse taxon sampling. We conclude that the loss of atp8 within flatworms is restricted to the parasitic taxon Neodermata.

Dataset Information

Reversible Valproate-Induced Subacute Encephalopathy Associated With a MT-ATP8 Variant in the Mitochondrial Genome.

Publications

Reversible Valproate-Induced Subacute Encephalopathy Associated With a <i>MT-ATP8</i> Variant in the Mitochondrial Genome.

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